Program Director/Principal Investigator (Last, First, Middle}: Lempka, Scott F PROJECT SUMMARY (See instructions}: Chronic pain is a major health problem in the United States and costs the nation upwards of $635 billion a year- more than cancer, heart disease and diabetes combined. Due to its debilitating nature and widespread impact, chronic pain is complex and challenging to treat. Unfortunately, conventional treatments have limited effectiveness for many people with severe chronic pain. Opioid analgesics are frequently prescribed despite the lack of evidence supporting their long-term use to treat chronic pain, and the associated opioid epidemic threatening the United States. Nonpharmacologic approaches, such as complementary and neurostimulation therapies, may offer better alternatives for chronic pain management. Spinal cord stimulation (SCS) is one type of neurostimulation therapy that can be considered for patients who are refractory to other treatment options. However, the outcomes of SCS and other neurostimulation therapies remain mixed. These variable outcomes can be contributed to a potential placebo effect and a poor understanding of their mechanisms of action. The goal of this project is to identify the anti-nociceptive effects of SCS by conducting a placebo-controlled study in patients undergoing SCS for chronic pain management. Spinal and supraspinal pain processing will be assessed with outcome measures related to several aspects of pain and quantitative sensory testing of pain sensitivity. These measurements will be combined with patient-specific computational models of SCS that will include: 1) electric-field models to estimate the direct neural response to SCS and 2) spinal cord circuit models to estimate the effects of SCS on pain processing. Therefore, this project will implement a systematic, well-controlled, patient-specific approach to investigate segmental spinal and central pain-processing mechanisms and the placebo effect associated with SCS. This approach is necessary to improve our understanding of chronic pain and how to treat it. II will apply cutting-edge computational modeling techniques to answer critical scientific questions within a clinical setting. The results of this project will improve scientific understanding of neurostimulation for chronic pain, help optimize and individualize current technologies, and innovate future therapies that improve clinical outcomes. RELEVANCE (See instructions): Neurostimulalion therapies, such as spinal cord stimulation, can provide nonpharmacologic treatment options to the millions of Americans suffering from pain. However, these neurostimulation therapies can fail to provide adequate pain relief in a large number of people. Therefore, this project will combine detailed computational models with measures of pain modulation in patients to investigate therapeutic mechanisms of neurostimulation and provide knowledge necessary to improve its effectiveness for pain management.